Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis

R E S E A R C H

Open Access

Mildly elevated lactate levels are associated

with microcirculatory flow abnormalities

and increased mortality: a microSOAP post

hoc analysis

Namkje A. R. Vellinga

, E. Christiaan Boerma

, Matty Koopmans

, Abele Donati

, Arnaldo Dubin

,

Nathan I. Shapiro

, Rupert M. Pearse

, Peter H. J. van der Voort

, Arjen M. Dondorp

, Tony Bafi

, Michael Fries

,

Tulin Akarsu-Ayazoglu

, Andrius Pranskunas

, Steven Hollenberg

, Gianmarco Balestra

, Mat van Iterson

,

Farid Sadaka

, Gary Minto

, Ulku Aypar

, F. Javier Hurtado

, Giampaolo Martinelli

, Didier Payen

,

Frank van Haren

, Anthony Holley

, Hernando Gomez

, Ravindra L. Mehta

, Alejandro H. Rodriguez

,

Carolina Ruiz

, Héctor S. Canales

, Jacques Duranteau

, Peter E. Spronk

, Shaman Jhanji

, Sheena Hubble

,

Marialuisa Chierego

, Christian Jung

, Daniel Martin

, Carlo Sorbara

, Jan Bakker

, Can Ince

and for the

microSOAP study group

Abstract

Background:

Mildly elevated lactate levels (i.e., 1

–

2 mmol/L) are increasingly recognized as a prognostic finding in

critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed

at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative

hyperlactatemia, microcirculatory flow, and outcome.

Methods:

This study was a predefined subanalysis of a multicenter international point prevalence study on

microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP).

Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory

flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow)

to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements,

and outcome were analyzed.

Results:

In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels

≤

2 mmol/L (median [IQR] 1.04 [0.80

–

1.40] mmol/L) were included. Crude ICU mortality increased with each lactate

quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR

2.5, 95% CI 1.1

–

5.7,

P

= 0.027).

(Continued on next page)

* Correspondence:[email protected]

1

Department of Intensive Care Adults, Erasmus MC University Medical Center, Rotterdam, The Netherlands

2_{Department of Intensive Care, Medical Center Leeuwarden, P.O. Box 888,}

8901 BR Leeuwarden, The Netherlands

Full list of author information is available at the end of the article

(Continued from previous page)

Conclusions:

In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference

range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy

of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated

lactate levels.

Trial registration:

ClinicalTrials.gov, NCT01179243. Registered on August 3, 2010.

Keywords:

Lactate, Microcirculation, SDF imaging, Intensive care, Prevalence

Background

An elevated lactate level, classically defined as an arterial

lactate level > 2 mmol/L, is a well-known predictor of

adverse outcome in terms of organ dysfunction and

mortality in different subgroups of critically ill patients

[1

–

3]. Surviving Sepsis Campaign guidelines consider a

threshold of 1 mmol/L as an indicator of tissue

hypoper-fusion, but they suggest resuscitation to normalize

arterial lactate levels in patients with lactate levels >

4 mmol/L in order to improve outcome, based on the

principles of early goal-directed therapy [4

–

6]. Similarly,

in nonseptic patients, the value of lactate levels in

goal-directed resuscitation, as well as the additive value of

serial lactate measurements, is recognized [7

–

10].

Recent studies indicate that small increases in lactate

levels are already associated with an unfavorable clinical

course. This association has been demonstrated for

“

relative hyperlactatemia

”

with thresholds as low as

1.1 mmol/L [11

–

14]. Although lactate is easily measured

in daily practice, unraveling the underlying causative

mechanism

is often much

more difficult.

Organ

hypoperfusion is regarded as an important cause of

hyperlactatemia, although several other mechanisms also

play a significant role, ranging from accelerated aerobic

glycolysis to decreased lactate metabolism and

mito-chondrial and microcirculatory dysfunction [15].

Sublin-gual direct in vivo microscopy is a suitable method of

detecting microcirculatory derangements at the bedside

[16]. Several studies have demonstrated an association

between lactate levels and microcirculatory alterations in

subgroups of critically ill patients as well as in

experi-mental settings [17

–

25]. We previously demonstrated

that both microcirculatory derangements and arterial

lactate levels were independent predictors of mortality

in selected high-risk patients [26].

The aforementioned studies were primarily focused on

the early phase of intensive care unit (ICU) admission.

The significance of minimally elevated lactate levels as

well as concomitant microcirculatory dysfunction at a

later time point is unclear. Therefore, we aimed to

inves-tigate the significance of a single-spot arterial lactate

measurement and simultaneous in vivo microscopy in a

heterogeneous ICU population recruited from 36 ICUs

worldwide.

Methods

Patients and setting

This study was a post hoc analysis of a prospective

observational point prevalence study of the prevalence

and significance of microcirculatory alterations in a

heterogeneous ICU population (Microcirculatory Shock

Occurrence in Acutely ill Patients [microSOAP;

Clinical-Trials.gov identifier NCT01179243; registered on August

3, 2010 [26]). Thirty-six ICUs worldwide participated in

this study. Being a point prevalence study, data

collec-tion on patient characteristics and laboratory values, as

well as simultaneous sublingual sidestream dark-field

(SDF) imaging, was performed on a single day for all

pa-tients in a given ICU or ICU subunit. Lactate levels were

measured within a maximum of 4 h before or after SDF

imaging. For this substudy, patients with an arterial

lactate level

≤

2 mmol/L were included.

Ethics approval

Every participating center obtained ethics approval

according to local legislation. A copy of the ethics

approval was sent to the study coordinator before the

start of the study (

see

Additional file 1). Written

in-formed consent was obtained from all included subjects,

unless the local ethics committee specifically allowed a

waiver in this respect.

SDF imaging

three sublingual SDF image sequences of 10

–

20 seconds

was obtained for every patient. SDF imaging as well as

subsequent image analysis were performed in line with

international consensus [27, 28].

Statistical analysis

Analysis was focused on associations between lactate

levels, mortality, organ dysfunction, and

microcircula-tory alterations. An abnormal microcirculamicrocircula-tory blood

flow was predefined as a sublingual MFI < 2.6 for vessels

< 20

μ

m, being the lowest reported lower bound of the

95% CI of healthy volunteers. We defined this value a

priori for the analysis of the original microSOAP data. A

post hoc analysis confirmed this cutoff value as the

Youden index in an ROC curve [26]. This cutoff value

has been validated as clinically relevant [26, 29]. To

determine cutoff values for lactate levels for both

abnor-mal MFI and mortality, the AUC was calculated. These

cutoff values were subsequently tested in logistic

regres-sion analysis.

Backward stepwise logistic regression was employed to

detect determinants of a capillary MFI < 2.6. Predictors

with

P

< 0.25 in univariable logistic regression were used

for multivariable modeling (

see

Additional file 2 for

additional information on the statistical analysis). Tested

predictors included Sequential Organ Failure

Assess-ment (SOFA) score on the day of SDF imaging, Acute

Physiology and Chronic Health Evaluation II (APACHE

II) score on ICU admission, length of stay in the ICU

prior to SDF imaging (

≤

24 h and > 24 h), admission

diagnosis, the presence of sepsis at the time of SDF

imaging, Hb

≤

5.37 mmol/L, arterial lactate level >

1.5 mmol/L, heart rate, mean arterial pressure, fluid

balance, and vasopressor use. In case of nonlinearity

of the logit, variables were dichotomized. The

result-ing models were tested for multicollinearity. Hosmer

and Lemeshow goodness of fit was used to test the

fit of the model. Furthermore, the associations

be-tween lactate levels, microcirculatory dysfunction,

mortality, and organ dysfunction (SOFA, cumulative

vasopressor index [CVI] [30]) were described by

dividing the lactate measurements into quartiles. To

test for differences between normally distributed

variables, Student

’

s

t

test or the Mann-Whitney

U

test was performed. To compare dichotomous

vari-ables, Fisher

’

s exact test was applied. Distributions

across more than two groups were tested using the

nonparametric Kruskal-Wallis test. The data were

analyzed using IBM SPSS Statistics version 23.0

(IBM, Armonk, NY, USA) and Prism 5.04

(Graph-Pad Software, Inc., La Jolla, CA, USA) software and

are presented as the median [IQR] or mean ± SD,

unless indicated otherwise.

P

< 0.05 was considered

statistically significant.

Results

General characteristics

Out of 501 patients, arterial lactate levels were available

for 338 (67%) of patients. In 257 out of these 338

patients (76%), arterial lactate levels were

≤

2 mmol/L.

These patients, with median APACHE of 16 [10

–

23] and

median SOFA of 5 [3

–

8], were included for further

ana-lysis (Table 1). Surgery (35.4%) and sepsis (17.5%) were

the main reasons for ICU admission. Median arterial

lactate levels were 1.04 [0.80

–

1.40] mmol/L. ICU and

hospital mortality were 20.6% and 27.2%, respectively.

Lactate levels and mortality

Increases in ICU mortality were observed for every

lac-tate quartile (

≤

0.80 mmol/L, 12.9%; 0.81

–

1.04 mmol/L,

15.3%; 1.05

–

1.40 mmol/L, 15.4%; > 1.40 mmol/L, 39.7%;

P

< 0.001). Similar trends were observed for hospital

mortality (24.3% in the lowest quartile, 44.4% in the

highest quartile;

P

= 0.005) (

see

Fig. 1). The AUC was

0.65 (95% CI 0.56

–

0.73,

P

= 0.001) with a cutoff value of

1.42 mmol/L for ICU mortality (sensitivity 40%,

specifi-city 81%). The same cutoff value was seen for hospital

mortality with a sensitivity of 47% and a specificity of

81% (AUC 0.59, 95% CI 0.51

–

0.67,

P

= 0.025). Mortality

was at least almost twice as high for patients with an

ar-terial lactate level > 1.5 mmol/L as compared with

patients with a lower lactate level (ICU mortality 41.2%

vs. 15.5%,

P

< 0.001; hospital mortality 45.1% vs. 22.9%,

P

= 0.001).

Lactate levels and microcirculatory flow abnormalities

Patients with a capillary MFI < 2.6 (14%) had slightly

but nonsignificantly higher lactate levels than patients

with a higher MFI (1.11 [0.90

–

1.60] vs. 1.00 [0.80

–

1.40] mmol/L,

P

= 0.117). A nonsignificant trend

toward a higher prevalence of an abnormal

microcir-culation in the highest lactate quartile was observed

(

P

= 0.169) (Fig. 1). Hb was significantly lower in

pa-tients with an MFI < 2.6 (Hb 5.4 [5.2

–

6.8] vs. Hb 6.3

[5.5

–

7.1],

P

= 0.011). No significant differences with

respect to illness severity scores, hemodynamics,

vasopressor use or dose, reason for ICU admission, or

time in ICU prior to SDF imaging were observed.

Comparing patients with lactate levels

≤

1.5 mmol/L

and > 1.5 mmol/L, no significant differences were

ob-served for small vessel MFI; large vessel MFI; and

small vessel TVD, PVD, PPV, (perfused) De Backer

score, and heterogeneity index.

Multivariable logistic regression analysis for MFI < 2.6

CI 1.3

–

6.6,

P

= 0.008), and an arterial lactate level >

1.5 mmol/L (OR 2.5, 95% CI 1.1

–

5.7,

P

= 0.027). The AUC

for this three-variable model was 0.74 (95% CI 0.65

–

0.83,

P

= 0.001). The Hosmer and Lemeshow chi-square

statistic was 2.015 (

P

=0.847) (

see also

Additional file 2).

Lactate levels and organ dysfunction

A higher lactate level was not accompanied by a

signifi-cantly higher SOFA score or CVI (

P

= 0.078 and

P

= 0.063,

respectively) (Figs. 2 and 3).

Different phenotypes

Although an abnormal MFI and elevated lactate levels

appear to be associated, several different phenotypes

exist. For individual patients, a higher lactate level

was not necessarily associated with adverse outcome

or an abnormal microcirculation or vice versa,

point-ing toward a multifactorial etiology and significance

of both hyperlactatemia and microvascular

derange-ments (Fig. 4).

Table 1

Patient characteristics

Characteristics Data

Age, years 64 [52–74]

Male sex,n(%) 156 (61)

APACHE II scorea 16 [10–23]

SOFA scoreb 5 [3–8]

ICU mortality,n(%) 53 (20.6)

In-hospital mortality,n(%) 70 (27.2)

Time in ICU before SDF imaging, days 4.0 [0.8–9.0]

<24 h in ICU before SDF imaging,n(%) 79 (30.7)

Reason for ICU admission,n(%)

Surgery 91 (35.4)

Sepsis 45 (17.5)

Cardiac disease 18 (7.0)

Neurological disorders 27 (10.5)

Trauma 30 (11.7)

Respiratory insufficiency 21 (8.2)

Other 25 (9.7)

Arterial lactate, mmol/L 1.04 [0.80–1.40]

Hemoglobin, mmol/L 6.2 [5.4–7.0]

Vasopressor drugs

Patients treated,n(%) 89 (34.6)

Cumulative vasopressor indexc 3 [2–4]

Mechanical ventilation,n(%) 161 (63)

Abnormal microcirculationd,n(%) 36 (14)

MFI small vessels, AU 2.9 [2.7–3.0]

MFI large vessels, AU 3.0 [2.9–3.0]

TVD, mm/mm2(small vessels) 18.9 [15.7–21.2] PVD, mm/mm2(small vessels) 18.1 [15.0–20.6]

PPV, % (small vessels) 98 [95–99]

De Backer score (small vessels) 11.3 ± 2.5

De Backer score (perfused small vessels) 10.9 ± 2.4

Heterogeneity index (small vessels) 0.07 [0.00–0.25]

Abbreviations: APACHE IIAcute Physiology and Chronic Health Evaluation II,ICU

Intensive care unit,MFIMicrovascular flow index,PPVPercentage of perfused

vessels,PVDPerfused vessel density,SDFSidestream dark-field imaging,SOFA

Sequential Organ Failure Assessment,TVDTotal vessel density

Values are mean ± SD or median [IQR] unless specified otherwise. Cutoff value for small vessels < 20μm

a

APACHE II scores range from 0 to 71, with higher values indicating more severe disease

b

SOFA scores range from 0 to 4 for each organ system, with higher scores indicating more severe organ dysfunction

c

Trzeciak et al. [30] d

Abnormal microcirculation defined as small vessel MFI < 2.6

Fig. 1Arterial lactate levels (quartiles) and distribution of intensive care unit (ICU)/hospital mortality and abnormal microvascular flow index (MFI < 2.6).P< 0.001 for ICU mortality,P= 0.005 for hospital mortality,P= 0.169 for abnormal MFI for distributions over quartiles

Discussion

In the present study, a single-spot arterial lactate level >

1.5 mmol/L was associated with increased mortality as

well as with microcirculatory abnormalities and organ

dysfunction. This

“

relative hyperlactatemia

”

is an

emer-ging concept [11

–

14, 31]. Lactate levels on admission as

low as 1.1 mmol/L already appeared to be associated

with adverse outcome [12]. Our observations add to the

idea that the prognostic relevance of mildly elevated

lactate levels is not restricted to the early phase of ICU

admission. The twofold increase in mortality in patients

with a lactate level > 1.5 mmol/L is in agreement with

results of previous studies focused on the first day of

ICU admission [13, 14]. Researchers in a few studies

have reported lactate levels and their association with

outcome during the later phase of ICU stay, showing

contradictory results. Some have observed an association

between hyperlactatemia after initial stabilization with

higher mortality rates, whereas others found that not

lactate itself but impaired lactate clearance was

associ-ated with adverse outcome [32, 33]. In this respect, it is

notable that we were able to demonstrate this

associ-ation in a highly heterogeneous study populassoci-ation, in

terms of both the timing of the lactate measurement as

well as the underlying diagnosis and disease severity.

Not only mortality but also organ dysfunction in terms

of SOFA score appeared to be more severe for increasing

lactate levels, albeit that this was statistically

nonsignifi-cant. A previous study was able to show associations

between incremental lactate levels > 2 mmol/L and

SOFA scores [2]. However, in that study, the

investiga-tors evaluated the time course of lactate measurements,

whereas in the present study, we evaluated the

implica-tions of a single lactate measurement.

Several mechanisms may be involved in the increase of

lactate levels. One of these, microcirculatory flow

abnor-malities, was indeed associated with mildly elevated

lactate levels in the present study. PVD, and therefore

effective diffusion distance, did not differ between

pa-tients with and without mildly elevated lactate levels.

Therefore, impaired convective oxygen transport, but

not diffusion distance, might have contributed to

anaer-obic glycolysis. Several researchers have also observed an

association between impairment of microvascular flow

and elevations in arterial lactate, whereas others have

been able to demonstrate associations between lactate

levels and parameters of vessel density in a variety of

disease states [17, 19

–

25].

Alternatively, several non-flow-related factors may

lead to increased nonanaerobic lactate formation

under conditions of stress by promoting conversion

of glucose to lactate via pyruvate instead of pyruvate

entering the citric acid cycle [15, 34]. Indeed, lactate

formation in endotoxemia results predominantly from

increased aerobic lactate formation [35]. On top of

that, exogenous adrenergic stress resulting from

β

-adrenergic drugs can also increase aerobic lactate

for-mation [36].

Besides ongoing lactate formation, impaired lactate

clearance has to be kept in mind as a cause of mildly

el-evated lactate levels. Levraut and coworkers observed

that in stable septic patients in whom arterial lactate

levels were < 2 mmol/L after the initial resuscitation

phase, impaired clearance of exogenous sodium lactate

but not baseline lactate values could discriminate

between survivors and nonsurvivors [32, 37]. It is

con-ceivable that a similar mechanism was involved in our

patients.

Fig. 3Cumulative vasopressor index (CVI) per arterial lactate quartile.

P= 0.063 for distributions over quartiles

Altogether, the direct observation of the

microcircu-lation in conjunction with lactate measurements

con-firms the idea that impaired organ perfusion is only one

of many explanations for elevated lactate levels with

potential consequences for therapeutic strategies in the

ICU [29, 38].

Our study has several limitations. At first glance, the

absolute numbers of lactate and MFI seem to indicate

that the study population was not severely ill. However,

owing to the design of the study, patients with a longer

stay in the ICU before study inclusion were

overrepre-sented. Therefore, the median APACHE II score of 16

seems to be a better indicator of considerable severity

of illness of the population at ICU admission. The lack

of macrohemodynamic monitoring limited in-depth

statistical analysis of factors associated with relative

hyperlactatemia. Furthermore, no detailed information

on factors influencing lactate clearance or drugs

influ-encing lactate metabolism (e.g., metformin) was

avail-able. In addition, the presence of microvascular flow

abnormalities in other organs not detected by

sublin-gual in vivo microscopy cannot be ruled out [39]. Serial

measurements of both microcirculation and lactate

could have shed more light on the time course of organ

dysfunction in patients with relative hyperlactatemia

[30, 40, 41]. Although independently associated in the

multivariate analysis, it is conceivable that a factor not

accounted for in our model influenced both lactate and

MFI. Last, it should be stated that the observed

associ-ation between relatively low lactate levels and outcome

does not automatically imply clinical relevance. Not

only is the predictive value of this multivariate model

relatively low with an AUC of 0.74, but it also remains

to be established whether interventions aimed at

achieving a further reduction of lactate will be

benefi-cial to patients.

Conclusions

Our data indicate that even single-spot lactate levels

within the usual reference range are associated with an

unfavorable clinical course. However, the question

remains how the clinician must incorporate these

find-ings into an individualized approach to treating

other-wise seemingly stable ICU patients. In vivo microscopy

of the (sublingual) microcirculation may be helpful for

detection of organ perfusion-related causes of mildly

elevated lactate levels with potential consequences for a

therapeutic strategy.

Additional files

Additional file 1:Declarations of ethical approval. (DOCX 23 kb)

Additional file 2:Supplemental material. (DOCX 14 kb)

Abbreviations

APACHE II:Acute Physiology and Chronic Health Evaluation II;

CVI: Cumulative vasopressor index; Hb: Hemoglobin; ICU: Intensive care unit; MFI: Microvascular flow index; microSOAP: Microcirculatory Shock Occurrence in Acutely ill Patients; PPV: Percentage of perfused vessels; PVD: Perfused vessel density; SDF: Sidestream dark-field imaging; SOFA: Sequential Organ Failure Assessment; TVD: Total vessel density

Acknowledgements

We thank Prof. J. L. Vincent, Department of Intensive Care, Erasme University Hospital, Brussels, Belgium, for allowing us to use the SOAP acronym in our study; F. Messie, Osix, Huizen, The Netherlands, for software engineering; A. Carsetti, MD, R. Domizi, MD, and C. Scorcella, MD, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Ancona, Italy; G. Veenstra, MD, and B. Scheenstra, MD, ICU, Medical Center Leeuwarden, Leeuwarden, The Netherlands, for their contributions to SDF analysis; D. M. J. Milstein, PhD, and K. Yuruk, MD, Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands for their help with SDF imaging; P. Ormskerk, RN, and D. van Duijn, RN, Intensive Care Adults, Erasmus MC University Medical Center Rotterdam, The Netherlands, for their help with study logistics; and D. S. Martin, MD, PhD, P. Meale, RGN, University College London, ICU, Royal Free Hospital, London, UK, and A. Vivian-Smith, RGN, ICU, Royal London Hospital, London, UK, for their assistance with UK ethics approval.

Participating centers and members of the microSOAP study group:

ICU, Medical Center Leeuwarden, Leeuwarden, The Netherlands (E. C. Boerma, MD, PhD, M. Koopmans, RN; N. A. R. Vellinga, MD)

ICU, St. Antonius Hospital, Nieuwegein, The Netherlands (M. van Iterson, MD, PhD)

ICU, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (P. H. J. van der Voort, MD, PhD)

ICU, Erasmus Medical Center, Rotterdam, The Netherlands (J. Bakker, MD, PhD; J. van Bommel, MD, PhD)

ICU, Gelre Ziekenhuizen, Apeldoorn, The Netherlands (P. E. Spronk, MD, PhD, FCCP)

Departamento de Medicina Intensiva, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (C. Ruiz, MD; G. Hernandez, MD, PhD)

Departamento de Anestesiologia, Dor e Terapia Intensiva, Hospital Sao Paulo, Universidade Federal de São Paulo Sao Paulo, Brazil (F. R. Machado, MD, PhD; A. T. Bafi, MD)

Servicio de Terapia Intensiva, Sanatorio Otamendi y Miroli, Buenos Aires, Argentina (A. Dubin, MD, PhD; V. S. Kanoore Edul, MD)

ICU, Hospital San Martín, La Plata, Argentina (H. S. Canales, MD)

ICU, Hospital Español‘Juan J Crotoggini’, Montevideo, Uruguay (F. J. Hurtado, MD; G. Lacuesta, MD; M. Baz, MD)

ICU, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ, USA (S. M. Hollenberg MD, FACC, FCCM, FAHA, FCCP; U. Patel, MD) ICU, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA (N. I. Shapiro, MD, MPH)

Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA (H. Gomez, MD; M. Pinsky, MD, CM, Dr hc, MCCM, FCCP)

Critical Care Medicine/Neurocritical Care, Mercy Hospital St. Louis/St. Louis University Hospital, St. Louis, MO, USA (F. G. Sadaka, MD; K. Krause, RN) ICU, University of California, San Diego, San Diego, CA, USA (R. Mehta, MD, PhD)

Department of Internal Medicine I, Universitätsklinikum Jena, Friedrich-Schiller-University, Jena, Germany (C. Jung, MD)

Department of Surgical Intensive Care, University Hospital Aachen, Aachen, Germany (M. Fries, MD, PhD)

Adult Critical Care Unit, Royal London Hospital, London, UK (R. M. Pearse, MBBS, FRCA, FFICM; A. Smith, RGN)

ICU, Royal Free Hospital, London, UK (D. S. Martin, MD, PhD; P. Meale, RGN) ICU, The Royal Marsden Hospital, Chelsea, London, UK (S. Jhanji, MD, PhD) ICU, Derriford Hospital, Plymouth University Peninsula School of Medicine, Plymouth, UK (G. Minto, MD, FRCA)

ICU, New Cross Hospital, Wolverhampton, UK (G. Martinelli, MD; M. Lombrano, MD)

ICU, Royal Devon and Exeter Hospital, Exeter, UK (S. M. A. Hubble, MD; C. Thorn, PhD)

Care Centre, Corporacio Sanitaria I Universitaria Parc Tauli–Hospital de Sabadell, Barcelona, Spain])

Department of Intensive Care Medicine, Waikato Hospital, Hamilton, New Zealand (F. M. P. van Haren, MD, PhD [current affiliation: Intensive Care Unit, Canberra Hospital, Canberra, Australia])

Intensive Care Department, Lithuanian University of Health Sciences, Kaunas, Lithuania (A. Pranskunas, MD, PhD; V. Pilvinis, MD, PhD)

Clinica di Anestesia e Rianimazione, Azienda Ospedaliera-Universitaria Ospedali Riuniti, Ancona, Italy (A. Donati, MD)

Dipartimento di Anestesia, Rianimazione e Terapia Intensiva, Azienda Unità Locale Socio Sanitaria 9 (ULSS 9) Veneto, Treviso, Italy (C. Sorbara, MD; A. Forti, MD, A. Comin, PhD)

ICU, Santa Maria degli Angeli Hospital, Pordenone, Italy (M. L. Chierego, MD; T. Pellis, MD)

ICU, The University of Queensland and Royal Brisbane and Women’s Hospital, Brisbane, Australia (A. Holley, MD, FACEM, FCICM; J. Paratz, MD, PhD) Departement d’Anesthesie-Reanimation, Hôpitaux Universitaires Paris-Sud, Univer-sité Paris-Sud, Hôpital de Bicêtre Assistance Publique_–Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France, Paris, France (J. Duranteau, MD, PhD; A. Harrois, MD) Department of Anesthesiology, Critical Care and Mobile Emergency and Resuscitation Service (SMUR), Hôpital Lariboisière (AP-HP)/Université Paris 7 Diderot, Paris, France (D. Payen, MD, PhD; C. Damoisel, MD)

Medical ICU, University Hospital Basel, Basel, Switzerland (G. M. Balestra, MD; E. Bucher, MD)

Ispat Hospital, Rourkela, Orissa, India (R. Pattnaik)

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (A. M. Dondorp, MD, PhD; M. T. Herdman, MD, PhD)

ICU, Hacettepe University, Ankara, Turkey (U. Aypar MD, B. Ayhan, MD) ICU, Kosuyolu University, Istanbul, Turkey (T. Ayazoglu-Akarsu, MD) The work was performed in the ICUs of the hospitals named above in the microSOAP study group affiliations and was coordinated from the ICU of Medical Center Leeuwarden, Leeuwarden, The Netherlands.

Collaborating authors:

J. van Bommel G. Hernandez F. Machado V. Kanoore Edul G. Lacuesta M. Baz U. Patel M. Pinsky K. Krause A. Smith P. Meale M. Lombrano C. Thorn I. Martin-Loeches V. Pilvinis A. Forti A. Comin T. Pellis J. Paratz A. Harrois C. Damoisel E. Bucher R. Pattnaik M. T. Herdman B. Ayhan

Funding

This study was supported in part by an unrestricted grant from the local hospital fund, Medical Center Leeuwarden, Leeuwarden, The Netherlands. The funder had no role in the study design; data acquisition, analysis, interpretation, and review; or approval of the manuscript. No financial compensation was received by participating centers or persons who made additional contributions.

Availability of data and materials

The datasets generated during and/or analyzed during the present study is not publicly available, owing to further research based on this dataset, but they are available from the corresponding author on reasonable request.

Authors’contributions

NARV, ECB, MK, ADo, ADu, NIS, RMP, JB, and CI conceived of and designed the study. NARV, ECB, MK, ADo, ADu, NIS, MRP, TB, MF, TAA, AP, SHo, GB, MvI, PHJvdV, FS, GMi, UA, FJH, GMa, DP, FvH, AH, AMD, HG, RLM, AHR, CR, HSC, JD, PES, SJ, SHu, MC, CJ, DM, CS, JB, CI acquired data. NARV, ECB, MK, and CI were responsible for data analysis. NARV, ECB, MK, ADo, ADu, NIS, RMP, JB, and CI interpreted the data. NARV, ECB, and CI wrote the manuscript draft. All authors revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All centers obtained medical ethics approval via their local ethics committees. Written informed consent (or a waiver, if applicable) was obtained in accordance with local applicable law.

Consent for publication

Not applicable.

Competing interests

The institution of NARV and ECB has received grant support from a local hospital fund (Medical Center Leeuwarden, unrestricted grant). NIS has served as a board member for the Cumberland Data and Safety Monitoring Board. The institution of NIS has received grant support from Biosite, Cheetah Medical, Rapid Pathogen Screening, and Thermo Fisher Scientific. RMP has consulted for Massimo and Edwards Lifesciences and has lectured for Nestle Health Sciences. The institution of RMP has received grant support from Nestle Health Sciences, LiDCO, and Cephalon (some are equipment loans, not funding). DP has consulted for Vygon Italia. RLM has consulted for AbbVie, CSL Behring, AM-Pharma, Grifols, Ardea Biosciences, and GlaxoSmithKline; has provided expert testimony for Nell DyMott; has lectured for AbbVie; and has stock options with Astute Medical. The institution of RLM has received grant support from Spectral Medical, AlloCure, and Eli Lilly. AHR has served as a board member for MSD; has consulted and lectured for Pfizer, Astellas Pharma, Novartis, and Brahms; and has received support for travel from Pfizer, MSD, Astellas Pharma, Novartis, and Brahms. HSC has disclosed government work. The institution of JD has lectured for LFB Biopharmaceuticals. SHu is employed by Royal Devon and Exeter Hospital NHS Trust (intensive care consultant). CJ reports receiving (all outside the submitted work) grants and per-sonal fees from Actelion Pharmaceuticals, Bayer Healthcare, and ZOLL Medical, as well as personal fees from Boehringer Ingelheim, Vifor Pharma, Pfizer, Abbott Vas-cular, Boston Scientific, and Novartis. CS has disclosed government work. CI has developed SDF imaging and is listed as inventor on related patents commercial-ized by MicroVision Medical (MVM) under a license from the Academic Medical Center, Amsterdam, The Netherlands. CI has been a consultant for MVM in the past but has not been involved with this company for more than 5 years, except for still holding shares. Braedius Medical, a company owned by a relative of CI, has developed and designed a handheld microscope called CytoCam-IDF imaging. CI has no financial relationship with Braedius Medical of any sort (i.e., has never owned shares or received consultancy or speaker fees from Braedius Medical).

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Author details

1_{Department of Intensive Care Adults, Erasmus MC University Medical Center,}

Rotterdam, The Netherlands.2Department of Intensive Care, Medical Center Leeuwarden, P.O. Box 888, 8901 BR Leeuwarden, The Netherlands.

3_{Department of Biomedical Science and Public Health, Università Politecnica}

delle Marche, Ancona, Italy.4_{Sanatorio Otamendi y Miroli, Servicio de Terapia}

Intensiva, Azcuénaga 870, Buenos Aires, Argentina.5Department of Emergency Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.6_{Barts and The London School}

of Medicine and Dentistry, London, UK.7_{Department of Intensive Care, Onze}

Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.8Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.9_{Dor e Terapia Intensiva,}

Universidade Federal de São Paolo, São Paolo, Brasil.10_{Department of}

Anesthesia and Surgical Intensive Care, St. Vincenz Krankenhaus, Limburg, Germany.11S.B. Medeniyet University Göztepe Education and Research Hospital Kadıköy, Istanbul, Turkey.12_{Intensive Care Department, Lithuanian}

University of Health Sciences, Kaunas, Lithuania.13_{Section of Cardiology,}

University Hospital Basel, Basel, Switzerland.15_{Department of Anesthesiology,}

Intensive Care and Pain Management, St. Antonius Hospital, Nieuwegein, The Netherlands.16_{Critical Care Medicine/Neurocritical Care, Mercy Hospital St.}

Louis, St. Louis University Hospital, St. Louis, MO, USA.17Derriford Hospital, Plymouth University Peninsula School of Medicine, Plymouth, UK.18_Intensive

Care Unit, Hacettepe University, Ankara, Turkey.19_{Intensive Care Unit,}

Hospital Español-State Health Administration Service, School of Medicine, University of the Republic, Montevideo, Uruguay.20Department of Perioperative Medicine, Barts Heart Centre, St. Bartholomew’s Hospital, London, UK.21_{Department of Anesthesiology, Critical Care and Mobile}

Emergency and Resuscitation Service (SMUR), Hôpital Lariboisière Assistance Publique–Hôpitaux de Paris (AP-HP)/Université Paris 7 Diderot, Paris, France.

22_{Intensive Care Unit, Canberra Hospital, Canberra, Australia.}23_{Department of}

Intensive Care Medicine, Royal Brisbane & Women_’s Hospital, Brisbane, Australia.24_{Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA,}

USA.25School of Medicine, University of California, San Diego, San Diego, CA, USA.26_{Critical Care Department, Joan XXIII University Hospital, Tarragona,}

Spain.27_{Departamento de Medicina Intensiva, Escuela de Medicina, Facultad}

de Medicina, Universidad Católica de Chile, Santiago, Chile.28_{Intensive Care}

Unit, Hospital San Martín, La Plata, Argentina.29Departement d’Anesthesie-Reanimation, Hôpitaux Universitaires Paris-Sud, Université Paris-Sud, Hôpital de Bicêtre Assistance Publique_–Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, Paris, France.30_{Intensive Care Unit, Gelre Ziekenhuizen,}

Apeldoorn, The Netherlands.31Intensive Care Unit, The Royal Marsden Hospital, London, UK.32_{Intensive Care Unit, Royal Devon and Exeter Hospital,}

Exeter, UK.33_{Intensive Care Unit, Santa Maria degli Angeli Hospital,}

Pordenone, Italy.34_{Department of Cardiology, Universitätsherzzentrum}

Thüringen, Clinic of Internal Medicine I, Friedrich Schiller University Jena, Jena, Germany.35_{Division of Cardiology, Pulmonology, and Vascular}

Medicine, Medical Faculty, University Düsseldorf, Düsseldorf, Germany.

36_{Intensive Care Unit, Royal Free Hospital, London, UK.}37_{Dipartimento di}

Anestesia, Rianimazione e Terapia Intensiva, Azienda Unità Locale Socio Sanitaria 9 (ULSS 9) Veneto, Treviso, Italy.

Received: 8 September 2016 Accepted: 15 September 2017

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